Treatment of cancer with specific RXR agonists

ABSTRACT

A method of treating cancer is disclosed comprising administering to a patient in need of such treatment a RXR agonist at a level below the RAR activating threshold and at or above the RXR effective dose.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 13/323,510 filed Dec. 12, 2011, which is a divisional of U.S.patent application Ser. No. 12/079,938 field Mar. 28, 2008 and now U.S.Pat. No. 8,101,662, which is a continuation-in-part of InternationalApplication PCT/US2006/038252 filed Oct. 2, 2006, which claims thebenefit of U.S. Provisional Patent Application 60/722,264 filed Sep. 30,2005. The contents of each of these applications are incorporated byreference herein in their entirety.

BACKGROUND

Compounds which have retinoid-like biological activity are well known inthe art and are described in numerous United States patents including,but not limited to, U.S. Pat. Nos. 5,466,861; 5,675,033 and 5,917,082,all of which are herein incorporated by reference. Preclinical studieswith rexinoids suggest that selective activation of retinoid X receptors(RXR), which modulate functions associated with differentiation,inhibition of cell growth, apoptosis and metastasis, may be useful intreating a variety of diseases associated with the biochemical functionsmodulated by RXR.

For example, TARGRETIN® (bexarotene), which is a RXR agonist with RARagonist activity as well, was approved by the U.S. Food and DrugAdministration for the treatment, both oral and topical, of cutaneousmanifestations of cutaneous T-cell lymphoma in patients who arerefractory to at least one prior systemic therapy. Further, recentclinical studies that were conducted using TARGRETIN® suggest that thereis potential for RXR agonists in the treatment of non-small cell lungcancer (NSCLC). Encouraging results were obtained with TARGRETIN® inseveral Phase II studies in NSCLC. However, the pivotal Phase IIIclinical study did not show increased survival. Therefore, there is aneed for new technologies that increase the efficacy of RXR agonistswhen used to treat solid tumors such as NSCLC.

SUMMARY

It is now proposed that activation of RAR by RXR agonists decreases theefficacy of the RXR agonists as anti-cancer agents. As such, theefficacy of treatment of cancer patients with RXR agonists can beimproved by administering the drug at a dose which activates RXR butwhich activates RAR minimally or not all. Based on this proposal, novelmethods of treating a patient with cancer are disclosed herein.

The present invention provides a method of treating cancer comprisingadministering to a patient in need of such treatment a RXR agonist at alevel below the RAR activating threshold and at or above the RXReffective dose.

In another embodiment, the present invention provides a method oftreating cancer comprising dosing a patient in need of such treatmentwith increasing concentrations of a RXR agonist to determine the RARactivating threshold and the RXR effective dose for the patient; andadministering to the patient the RXR agonist at a level below the RARactivating threshold and at or above the RXR effective dose.

In yet another embodiment, the present invention provides a method fortreating cancer comprising the step of administering to a patient inneed of such treatment an effective amount of a RXR agonist having atherapeutically beneficial mean RXR EC₉₀:RAR EC₁₀ ratio range. Atherapeutically beneficial mean RXR EC₉₀:RAR EC₁₀ ratio is at leastabout 40. Alternatively, a therapeutically beneficial mean RXR EC₉₀:RAREC₁₀ ratio is at least about 100. In another alternative, atherapeutically beneficial mean RXR EC₉₀:RAR EC₁₀ ratio is at leastabout 200.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-1D illustrate the effects of VTP 194204 on nude micexenografted with human H292 NSCLC tumors. Nude mice were randomized into4 groups of 10 animals each based on body weight and xenograftedsubcutaneously in the right flank with H292 cells (2×10⁶ cells). Drugtreatment was started immediately after xenografting and continued for35 days (5 animals of each group) or 55 days (remaining 5 animals). Theanimals were treated with vehicle (VEH), TAXOL®5 mg/kg/week, once aweek, i.p., VTP 194204 10 mg/kg/day, 5 days a week, by oral gavage, orVTP 194204+TAXOL®. Tumor sizes were measured periodically for 35 days(FIG. 1A). Animals #1-5 of each group were sacrificed after 35 days oftreatment and gastrocnemus muscles were determined (FIG. 10). The bodyweights and overall appearance of animals #6 through #10 from each groupwere followed for an extended period (FIG. 1B and FIG. 1D). Toappropriately show the overall health of these animals, pictures weretaken from their tumor-free left flank on day 55 (FIG. 1D).

DETAILED DESCRIPTION

To maximize efficacy, anticancer agents are most commonly administeredat or near to the maximum tolerated dose (MTD). It is now proposed thatcertain RXR agents can not only be efficaciously administered at dosessignificantly lower than MTD, but are actually more effective at theselower doses than at or near the MTD. As such, the efficacy of thetreatment can be enhanced while lowering side effects. Examples ofsuitable doses include: between about 0.1 to about 10 mg/m²/day; betweenabout 0.5 to about 2 mg/m²/day; between about 0.01-100 mg/m²/day;between about 1 to about 50 mg/m²/day; between about 0.1 mg/m²/day toabout 1.0 mg/m²/day; between about 1.0 mg/m²/day and about 5.0mg/m²/day; between about 5.0 mg/m²/day and about 10.0 mg/m²/day; betweenabout 10.0 mg/m²/day and about 15 mg/m²/day; between about 15.0mg/m²/day and about 20.0 mg/m²/day; between about 20.0 mg/m²/day andabout 25.0 mg/m²/day; between about 30.0 mg/m²/day and about 35.0mg/m²/day; between about 35.0 mg/m²/day and about 40.0 mg/m²/day;between about 40.0 mg/m²/day and about 45.0 mg/m²/day; between about45.0 mg/m²/day and about 50.0 mg/m²/day; between about 50.0 mg/m²/dayand about 55.0 mg/m²/day; between about 55.0 and about 60.0 mg/m²/day;between about 60.0 mg/m²/day and about 65.0 mg/m²/day; between about65.0 mg/m²/day and about 70.0 mg/m²/day; between about 70.0 mg/m²/dayand about 75.0 mg/m²/day; between about 75.0 mg/m²/day and about 80.0mg/m²/day; between about 80.0 mg/m²/day and about 85.0 mg/m²/day;between about 85.0 and about 90.0 mg/m²/day; between about 85.0mg/m²/day and about 90.0 mg/m²/day; between about 90.0 mg/m²/day andabout 95.0 mg/m²/day; and between about 95.0 mg/m²/day and about 100.0mg/m²/day.

DEFINITIONS

CYP26 means Cytochrome P450 Type 26.

CRBPI means Cellular Retinol Binding Protein.

The RXR agonists can optionally be administered in the disclosed methodsin combination with a second anti-cancer agent. Suitable anti-canceragents include cytotoxic drugs, including, but not limited to, TAXOL®(paclitaxel), TAXOTERE® (docetaxel), and the like and mixtures thereof.Additional anti-cancer agents include Adriamycin, Dactinomycin,Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazolehydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;interleukin 11 (including recombinant interleukin 11, or rIL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred additional anti-cancer drugs are 5-fluorouraciland leucovorin.

Platinum based drugs include, but are not limited to, carboplatin,cisplatin, and the like and mixtures thereof.

RAR means one or more of RAR α, β and γ.

RXR means one or more of RXR α, β and γ.

A RAR biomarker is a distinctive biological, biochemical or biologicallyderived indicator that signifies patient RAR activity. RAR biomarkersinclude, but are not limited to, CYP26 levels, CRBPI levels and the likeand combinations thereof.

RAR activation threshold means one or more of the following: a CYP26level of a 2-fold increase over baseline, and a CRBPI level of a 2-foldincrease over baseline.

RXR EC₉₀:RAR EC₁₀ ratio is calculated by taking the inverse of the RXREC₉₀ α, β and γ values (nM) divided by the corresponding inverse of theRAR EC₁₀ α, β and γ values (nM). For example, the RXR EC₉₀:RAR EC₁₀ratio is determined by dividing RAR EC₁₀ by RXR EC₉₀ for α, β and γ.Thus, a value is obtained for all three receptors, referred to herein as(RXR EC₉₀:RAR EC₁₀ ratio)_(α), (RXR EC₉₀:RAR EC₁₀ ratio)_(β) and (RXREC₉₀:RAR EC₁₀ ratio)_(γ) for α β and γ, respectively. For example, (RXREC₉₀:RAR EC₁₀ ratio), is determined by dividing RAR EC₁₀α by RXRα EC₉₀.The mean RXR EC₉₀:RAR EC₁₀ ratio is the average of all three values. Anexample is provided below in Tables 1A and 1B.

TABLE 1(A) Comparison of safety margins of VTP 194204 and TARGRETIN ®.RXR EC₉₀ and RAR EC₁₀ values of VTP 194204 and TARGRETIN ®. RXR RAR EC₉₀(nM) EC₁₀ (nM) Compound α β γ α β γ VTP 194204 0.1 1 0.1 300 200 200TARGRETIN ® 15 100 15 1000 200 300

TABLE 1(B) Comparison of safety margins of VTP 194204 and TARGRETIN ®.Ratio of RXR EC90 to RAR EC10 for VTP 194204 and TARGRETIN ®. RXREC₉₀:RAR EC₁₀ ratio Compound α β γ Mean VTP 194204 3000 200 2000 1730TARGRETIN ® 67 2 20 30Table 1

RXR effective dose means the dose needed to fully activate RXRs asascertained by pharmacodynamic markers (RXR biomarkers) such asreductions in TSH levels.

Representative examples of RXR agonists for use herein and processes fortheir preparation are well known in the art, e.g., in U.S. Pat. Nos.5,663,367; 5,675,033; 5,780,647; 5,817,836; 5,917,082; 6,034,242;6,048,873; 6,114,533; 6,147,224; 6,313,163; 6,403,638 and 6,720,423, thecontents of each of which are incorporated by reference herein in theirentirety. Many of the following compounds are included in one or more ofthese applications.

A class of compounds for use herein is represented by Formula I:

wherein Z is a radical shown in Formula II,

Y is selected from thienyl and furyl, the groups being optionally withone or two R₄ groups, the divalent Y radical being substituted by the Zand —(CR₁═CR₁—CR₁═CR₁)— groups on adjacent carbons; n is 1 or 2; R₁ andR₂ independently are H, lower alkyl or fluoroalkyl; R₃ is hydrogen,lower alkyl, Cl or Br; R₄ is lower alkyl, fluoroalkyl or halogen, and Bis hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR₈,CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, OCOR₇,CR₇(OR₁₂)₂, CR₇OR₁₃O, or tri-lower alkylsilyl, where R₇ is an alkyl,cycloalkyl or alkenyl group, containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ carbons, or a cycloalkyl groupsof 5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl,phenyl or lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalentalkyl radical of 2-5 carbons.

Another class of compounds for use herein is represented by Formula III:

wherein R₂ is hydrogen or lower alkyl; R₃ is hydrogen or lower alkyl,and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CHOH, CHOR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or tri-lower alkylsilyl, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons.

Another class of compounds for use herein is represented by Formula IV:

wherein n is 1 or 2; R₁ and R₂ independently are H, lower alkyl orfluoroalkyl; R₃ is hydrogen, lower alkyl, Cl or Br; R₄ is H, loweralkyl, fluoroalkyl or halogen, and B is hydrogen, COOH or apharmaceutically acceptable salt thereof, COOR₈, CONR₉R₁₀, —CH₂OH,CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂,CR₇OR₁₃O, or trilower alkylsilyl where R₇ is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl,phenyl or lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalentalkyl radical of 2-5 carbons.

Another class of compounds for use herein is represented by Formula V:

where R₄ is lower alkyl of 1 to 6 carbons; B is COOH or COOR₈ where R₈is lower alkyl of 1 to 6 carbons, and the configuration about thecyclopropane ring is cis, and the configuration about the double bondsin the pentadienoic acid or ester chain attached to the cyclopropanering is trains in each of the double bonds, or a pharmaceuticallyacceptable salt of the compound.

Another class of compounds for use herein is represented by Formula VI:

wherein Z is a radical shown in Formula VII:

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R₄ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, the groups being optionally substituted withone or two R₄ groups, the divalent Y radical being substituted by the Zand —CR₁═CR₁—CR₁═CR₁)— groups on adjacent carbons; X is S or O; R₁ andR₂ independently are H, lower alkyl or fluoroalkyl; R₃ is hydrogen,lower alkyl, Cl or Br; R₄ is lower alkyl fluoroalkyl or halogen, and Bis hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR₈,CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, —COR₇,CR₇(OR₁₂)₂, CR₇OR₁₃O, or trilower alkylsilyl, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of2-5 carbons.

Another class of compounds for use herein is represented by FormulaVIII:

wherein X is S or O; R₂ is hydrogen or lower alkyl; R₃ is hydrogen orlower alkyl, and B is hydrogen, COOH or a pharmaceutically acceptablesalt thereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO,CH(OR₁₂)₂, CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or trilower alkylsilyl,where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5carbons, R₈ is an alkyl group of 1 to 10 carbons, a cycloalkyl group of5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl,phenyl or lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalentalkyl radical of 2-5 carbons.

Another class of compounds for use herein is represented by Formula IX:

wherein Z is selected from the group consisting of the radicals aradical shown in Formulae X and XI:

Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups beingoptionally substituted with one or two R₄ groups, the divalent Y radicalbeing substituted by the Z and —CR₁═CR₁—CR₁═CR₁)— groups on adjacentcarbons; X is NR₅; n is 1 or 2; R₁ and R₂ independently are H, loweralkyl or fluoroalkyl; R₃ is hydrogen, lower alkyl, Cl or Br; R₄ is loweralkyl, fluoroalkyl or halogen; R₅ is H or lower alkyl, and B ishydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR₈,CONR₉R.₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₂)₂, CHOR₁₃O, —COR₇,CR₇(OR₁₂)₂, CR₇OR₁₃O, or trilower alkylsilyl, where R₇ is an alkyl,cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is an alkylgroup of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R₈ isphenyl or lower alkylphenyl, R₉ and R₁₀ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of 2to 5 carbons.

Another compound for use herein is enantiomerically substantially purecompound of Formula XII:

wherein R is H, lower alkyl or 1 to 6 carbons, or a pharmaceuticallyacceptable salt of the compound.

Another class of compounds for use herein is represented by FormulaXIII:

wherein Z is the group shown in Formula XIV:

Y is cyclopropyl, the Y group being optionally substituted with one ortwo R₄ groups, the divalent Y radical being substituted by the Z and—(CR₁═CR₁—CR₁═CR₁)— groups on adjacent carbons; X is NR₅; R₁ and R₂independently are H, lower alkyl or fluoroalyl; R₃ is hydrogen, loweralkyl, Cl or Br; R₄ is lower alkyl, fluoroalkyl or hydrogen; R₅ is H orlower alkyl, and B is hydrogen, COOH or a pharmaceutically acceptablesalt thereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO,CH(OR₁₂)₂, CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or trilower alkylsilyl,where R₇ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5carbons, R₈ is an alkyl group of 1 to 10 carbons, a cycloalkyl group of5 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl,phenyl or lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalentalkyl radical of 2 to 5 carbons.

Another class of compounds for use herein is represented by Formula XV:

wherein X is NR₅; R₅ is H or lower alkyl; R₂ is H or lower alkyl; R₃ isH or lower alkyl, and B is hydrogen, COOH or a pharmaceuticallyacceptable salt thereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁,CHO, CH(OR₁₂)₂, CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or triloweralkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons, a cycloalkylgroup of 5 to 10 carbons or trimethylsilylalkyl where the alkyl grouphas 1 to 10 carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀independently are hydrogen, an alkyl group of 1 to 10 carbons, or acycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ islower alkyl, phenyl or lower alkylphenyl, R₁₂ is lower alkyl, andR.sub.₁₃ is divalent alkyl radical of 2 to 5 carbons.

Another class of compounds for use herein is represented by Formula XVI:

where Y is a bivalent radical having Formula XVII

the two X₁ groups jointly represent an oxo (═O) or thione (═S) function,or X₁ is independently selected from H or alkyl of 1 to 6 carbons; thetwo X₂ groups jointly represent an oxo (═O) or a thione (═S) function,or X₂ independently selected from H or alkyl of 1 to 6 carbons, with theproviso that one of the joint X₁ grouping or of the joint X₂ groupingrepresents an oxo (═O) or thione (═S) function; W is O, C(R₁)₂, or Wdoes not exist; R₁ is independently H, lower alkyl of 1 to 6 carbons, orlower fluoroalkyl of 1 to 6 carbons; R₂ is independently H, lower alkylof 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R₃ ishydrogen, lower alkyl of 1 to 6 carbons, OR₁, fluoro substituted loweralkyl of 1 to 6 carbons halogen, NO₂, NH₂, NHCO(C₁-C₆ alkyl, orNHCO(C₁-C₆) alkenyl; A is hydrogen, COOH or a pharmaceuticallyacceptable salt thereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁,CHO, CH(OR₁₂)₂, CH(OR₁₃O), —COR₇, CR₇(OR₁₂)₂, CR₇(OR₁₃O), orSi(C₁-6alkyl)₃, where R₇ is an alkyl, cycloalkyl or alkenyl groupcontaining 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or(trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or loweralkyphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,hydroxyphenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenyl or loweralkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkyl radical of 2to 5 carbons, and R₁₄ is H, alkyl of 1 to 10 carbons, fluoro-substitutedalkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3double bonds.

Another class of compounds for use herein is represented by FormulaXVIII:

wherein R₁ is independently H, lower alkyl of 1 to 6 carbons, or lowerfluoroalkyl of 1 to 6 carbons; R₁* is hydrogen or C.sub.1-6-alkyl; R₂*is independently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkylof 1 to 6 carbons; R₃* is hydrogen, lower alkyl of 1 to 6 carbons,fluoro substituted lower alkyl of 1 to 6 carbons or halogen; X₁* is anoxo (═O) or a thione (═S) group; A* is hydrogen, COOH or apharmaceutically acceptable salt thereof, COOR₈, CONR₉R₁₀, where R₈ isan alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where thealkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, and thecyclopropyl group is attached to the 6 or 7 position of thetetrahydroquinoline moiety, and R₁₄* is alkyl of 1 to 10 carbons orfluoro-substituted alkyl of 1 to 10 carbons.

Another class of compounds for use herein is represented by FormulaeXIX, XX or XXI:

where X is O, S, or (CR₁R₁)_(n) where n is 0, 1 or 2; Y is a bivalentradical having Formulae XXII or XXIII where o is an integer between 1through 4

or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1to 3 heteroatoms selected from N, S and O, the aryl or heteroaryl groupsbeing unsubstituted, or substituted with 1 to 3 C₁₋₆ alkyl or with 1 to3 C₁₋₆ fluoroalkyl groups with the proviso that when the compound is inaccordance with Formula 2 then Y is not a 5 or 6 membered ring; X₁ is Sor NH; R₁ is independently H, lower alkyl of 1 to 6 carbons, or lowerfluoroalkyl of 1 to 6 carbons; R₂ is independently H, lower alkyl of 1to 6 carbons, OR₁, adamantly, or lower fluoroalkyl of 1 to 6 carbons, orthe two R₂ groups jointly represent an oxo (═O) group with the provisothat when the compound is in accordance with Formula 2 then at least oneof the R₂ substituents is branched-chain alkyl or adamantly; R₃ ishydrogen, lower alkyl of 1 to 6 carbons, OR₁, fluoro substituted loweralkyl of 1 to 6 carbons or halogen, NO₂, NH₂, NHCO(C₁-C₆ alkyl, orNHCO(C₁-C₆) alkenyl; A is COOH or a pharmaceutically acceptable saltthereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂,CH(OR₁₃O), —COR₇, CR₇(OR₁₂)₂, CR₇(OR₁₃O), or Si(C₁₋₈alkyl)₃, where R₇ isan alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ isan alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where thealkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons, and R₁₄is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double bonds,alkynyl having 2 to 10 carbons and 1 to 3 triple bonds, carbocyclic arylselected from the group consisting of phenyl, C₁-C₁₀-alkylphenyl,naphthyl, C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀alkyl,naphthyl-C₁-C₁₀alkyl, C₁-C₁₀-alkenylphenyl having 1 to 3 double bonds,C₁-C₁₀-alkynylphenyl having 1 to 3 triple bonds, phenyl-C₁-C₁₀alkenylhaving 1 to 3 double bonds, phenyl-C₁-C₁₀alkenyl having 1 to 3 triplebonds, hydroxyl alkyl of 1 to 10 carbons, hydroxyalkenyl having 2 to 10carbons and 1 to 3 double bonds, hydroxyalkynyl having 2 to 10 carbonsand 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenylhaving 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2to 10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons,acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double bonds, oracyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple bonds where the acylgroup is represented by COR₈, or R₁₄ is a 5 or 6 membered heteroarylgroup having 1 to 3 heteroatoms, the heteroatoms being selected from agroup consisting of O, S, and N, the heteroaryl group beingunsubstituted or substituted with a C₁ to C₁₀ alkyl group, with a C₁ toC₁₀ fluoroalkyl group, or with halogen, and the dashed line in FormulaXXII represents a bond or absence of a bond.

Another class of compounds for use herein is represented by FormulaeXXIV:

wherein R is H, lower alkyl of 1 to 6 carbons, or a pharmaceuticallyacceptable salt of the compound.

Another class of compounds for use herein is represented by FormulaeXXV:

wherein R is H, lower alkyl of 1 to 6 carbons, and R₁ is iso-propyl ortertiary-butyl, or a pharmaceutically acceptable salt of the compound.

Another class of compounds for use herein is represented by FormulaeXXVI:

wherein R is H, lower alkyl of 1 to 6 carbons, and R₁ is iso-propyl,n-butyl or tertiary-butyl, or a pharmaceutically acceptable salt of thecompound.

Another class of compounds for use herein is represented by FormulaeXXVII:

where X is O or S; Y is a bivalent cycloalkyl or cycloalkenyl radicaloptionally substituted with one to four R₄ groups, the cycloalkenylradical having 5 to 6 carbons and one double bond, or Y is a bivalentaryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatomsselected from N, S and O, the aryl or heteroaryl groups optionallysubstituted with 1 to 4 R₄ groups with the proviso that the cycloalkylor the cycloalkenyl radical is not substituted on the same carbon withthe condensed cyclic moiety and with the diene containing moiety; R₁ isindependently H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6carbons; R₂ is independently H, alkyl of 1 to 8 carbons, or fluoroalkylof 1 to 8 carbons; R₁₂ is independently H, alkyl of 1 to 8 carbons, orfluoroalyl of 1 to 8 carbons; R₃ is hydrogen, alkyl of 1 to 10 carbons,fluoro substituted alkyl of 1 to 10 carbons, halogen, alkoxy of 1 to 10carbons, or alkylthio of 1 to 10 carbons; NO₂, NH₂, NHCO(C₁-C₆ alkyl,NHCO(C₁-C₆) alkenyl, NR₁H or N(R₁)₂, benzyloxy, C₁-C₆alkyl-substitutedbenzyloxy, or R₃ is selected from the groups shown below,

R₄ is H, halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10carbons; m is an integer having the values of 0 to 3; r is an integerhaving the values of 1 to 10; s is an integer having the values 1 to 4;t is an integer having the values 1 to 5;

represents a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatomsselected from the group consisting of N, S and O; B is hydrogen, COOH ora pharmaceutically acceptable salt thereof, COOR₈, CONR₉R₁₀, —CH₂OH,CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂,CR₇OR₁₃O, or trilower alkylsilyl, where R₇ is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkylwhere the alkyl group has 1 to 10 carbons, or R₈ is phenyl or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2 to 5 carbons.

Another class of compounds for use herein is represented by FormulaeXXVIII:

wherein R₁H or methyl; R₈ is H, alkyl of 1 to 6 carbons, or apharmaceutically acceptable cation, and R₃ is hydrogen, alkyl of 1 to 10carbons, halogen, alkoxy of 1 to 10 carbons, or R₃ is selected from thegroups shown below

where R₄ is H, halogen, alkyl of 1 to 10 carbons, carbons, alkoxy of 1to 10; r is an integer having the values of 1 to 10; s is an integerhaving the values 1 to 4;

represents a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatomsselected from the group consisting of N, S and O, and t is an integerhaving the values 1 to 5.

A preferred compound for use herein is VTP 194204 which means3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-aphth-7-yl]2(E),4(E) heptadienoic acid, and has the following chemical structure:

Pharmaceutically acceptable salts of RXR agonists can also be used inthe disclosed method. Compounds disclosed herein which possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly can react with any of a number of organic or inorganicbases, and inorganic and organic acids, to form a salt.

Acids commonly employed to form acid addition salts from RXR agonistswith basic groups are inorganic acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, andthe like, and organic acids such as p-toluenesulfonic acid,methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonicacid, succinic acid, citric acid, benzoic acid, acetic acid, and thelike. Examples of such salts include the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenyl butyrate,citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate, and the like.

Bases commonly employed to form base addition salts from RXR agonistswith acidic groups include, but are not limited to, hydroxides of alkalimetals such as sodium, potassium, and lithium; hydroxides of alkalineearth metal such as calcium and magnesium; hydroxides of other metals,such as aluminum and zinc; ammonia, and organic amines, such asunsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine;diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkylamines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike.

TSH means thyroid stimulating hormone.

TSH modulating agents include, but are not limited to, rexinoids,thyroid hormones and the like and mixtures thereof.

The instant invention provides a method of treating cancer comprisingadministering to a patient in need of such treatment a RXR agonist at alevel below the RAR activating threshold and at or above the RXReffective dose.

In another embodiment, the invention provides a method of treatingcancer comprising dosing a patient in need of such treatment withincreasing concentrations of a RXR agonist to determine the RARactivating threshold and the RXR effective dose for the patient;administering to the patient the RXR agonist at a level below the RARactivating threshold and at or above the RXR effective dose.

Examples of cancers which can be treated by the disclosed methodsinclude Acute Lymphoblastic Leukemia, Adult; Acute LymphoblasticLeukemia, Childhood; Acute Myeloid Leukemia, Adult; AdrenocorticalCarcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma;AIDS-Related Malignancies; Anal Cancer; Astrocytoma, ChildhoodCerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer,Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer,Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma,Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma,Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor,Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor,Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; BrainTumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; BrainTumor, Visual pathway and Hypothalamic Glioma, Childhood; Brain Tumor,Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; BreastCancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids,Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor,Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell;Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary;Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/MalignantGlioma, Childhood; Cervical Cancer; Childhood Cancers; ChronicLymphocytic Leukemia; Chronic Myelogenous Leukemia; ChronicMyeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths;Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma;Endometrial Cancer, Ependymoma, Childhood; Epithelial Cancer, Ovarian;Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family ofTumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ CellTumor, Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma;Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach)Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal CarcinoidTumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor,Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor,Glioma, Childhood Brain Stem; Glioma, Childhood Visual pathway andHypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular(Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer,Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma,Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer;Hypothalamic and Visual pathway Glioma, Childhood; Intraocular Melanoma;Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; KidneyCancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, AcuteLymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood;Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood;Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia,Hairy Cell; Lip and Oral Cavity Cancer; Liver, Cancer, Adult (Primary);Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; LungCancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; LymphoblasticLeukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma,AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma,Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's,Childhood; Lymphoma, Hodgkin's During Pregnancy, Lymphoma,Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma,Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central NervousSystem; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; MalignantMesothelioma, Adult; Malignant Mesothelioma, Childhood; MalignantThymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular;Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous NeckCancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome,Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides;Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; MyeloidLeukemia, Childhood Acute; Myeloma, Multiple; MyeloproliferativeDisorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer,Nasopharyngeal Cancer, Nasopharyngeal Cancer, Childhood; Neuroblastoma;Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood;Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer,Oral Cancer, Childhood; Oral Cavity and Lip Cancer; OropharyngealCancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; OvarianCancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor;Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; PancreaticCancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus andNasal Cavity Cancer; Parathyroid Cancer; Penile Cancer,Pheochromocytoma; Pineal and Supratentorial Primitive NeuroectodermalTumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/MultipleMyeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma;Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult;Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; RenalCell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis andUreter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma,Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood;Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma(Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma,Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, SoftTissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood;Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell LungCancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft TissueSarcoma, Childhood; Squamous Neck Cancer with Occult Primary,Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer,Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood;T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood;Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood;Transitional Cell Cancer of the Renal Pelvis and Ureter; TrophoblasticTumor, Gestational; Unknown Primary Site, Cancer of, Childhood; UnusualCancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer;Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual pathway andHypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom'sMacroglobulinemia; and Wilms' Tumor. In a preferred embodiment, thecancer is non-small cell lung cancer, breast or prostate cancer.

In another preferred embodiment, the RXR effective dose can bedetermined by the reduction of the patient's thyroid stimulating hormone(TSH) levels.

In yet another preferred embodiment, the RAR activating threshold can bedetermined by measuring at least one RAR biomarkers expressed by thepatient.

In still yet another preferred embodiment, the RAR biomarker is selectedfrom the group consisting of CYP26 level, CRBPI level, and combinationsthereof.

In yet another preferred embodiment, the invention further includesmeasuring the patient's C_(max) of the RXR agonist and adjusting thedose to maintain the patient's C_(max) at an optimal level.

In one embodiment, the RXR agonist is TARGRETIN®. In another embodiment,the RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-aphth-7-yl]2(E),4(E)heptadienoic acid.

If desired, the methods can further include treating the patient with atleast one other anti-cancer agent. Preferred anti-cancer agents include,but are not limited to, a platinum-based compound, a cytotoxic drug andthe like and mixtures thereof.

In a preferred embodiment, the method further includes treating thepatient with one or more triglyceride lowering agents.

In a preferred embodiment, the method further includes treating thepatient with one or more TSH modulating agents.

In another embodiment, the invention provides a method for treatingcancer via modulation of RXR including at least the step ofadministering to a patient in need of such treatment an effective amountof a RXR agonist having a therapeutically beneficial RXR EC₉₀:RAR EC₁₀ratio range. In a preferred embodiment, the mean of the RXR EC₉₀:RAREC₁₀ ratio is at least about 40. In a more preferred embodiment, themean of the RXR EC₉₀:RAR EC₁₀ ratio is at least about 200.Alternatively, the RXR EC₉₀:RAR EC₁₀ ratio for one of α, β and γ is atleast about 40. More preferably, the RXR EC₉₀:RAR EC₁₀ ratio for one ofα, β and γ are all at least about 200. Typically, the (RXR EC₉₀:RAR EC₁₀ratio)_(□) is at least 40, more typically at least 200. In anotheralternative, the RXR EC₉₀:RAR EC₁₀ ratio for α, β and γ are all at leastabout 40. More preferably, the RXR EC₉₀:RAR EC₁₀ ratio for α, β and γare all at least about 200.

A “patient” is a mammal, preferably a human, but can also be an animalin need of veterinary treatment, e.g., companion animals (e.g., dogs,cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, andthe like) or laboratory animals (e.g., rats, mice, guinea pigs, and thelike).

The RXR agonist compounds for use in the methods of the presentinvention may be used as is or incorporated into a pharmaceuticalcomposition. All modes of administrations are contemplated, e.g.,orally, rectally, parenterally, topically, or by intravenous,intramuscular, intrasternal or subcutaneous injection or in a formsuitable by inhalation. The formulations may, where appropriate, beconveniently presented in discrete dosage units and may be prepared byany of the methods well known in the art of pharmacy. The compounds willordinarily be formulated with one or more pharmaceutically acceptableingredients in accordance with known and established practice. Thus, thepharmaceutical composition can be formulated as a liquid, powder,elixir, injectable solution, suspension, suppository, etc.

Formulations for oral use can be provided as tablets or hard capsuleswherein the compounds are mixed with an inert solid diluent such ascalcium carbonate, calcium phosphate or kaolin, or as soft gelatincapsules wherein the active ingredients are mixed with water or misciblesolvents such as propylene glycol, PEGs and ethanol, or an oleaginousmedium, e.g., peanut oil, liquid paraffin or olive oil.

For topical administration in the mouth, the pharmaceutical compositionscan take the form of buccal or sublingual tablet, drops or lozengesformulated in conventional manner.

For topical administration to the epidermis, the compounds can beformulated as creams, gels, ointments or lotions or as transdermalpatches. Such compositions can, for example, be formulated with anaqueous or oily base with the addition of suitable thickening, gelling,emulsifying, stabilizing, dispersing, suspending, and/or coloringagents.

The compounds can also be formulated as depot preparations. Such longacting formulations can be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds can be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, for exampleas a sparingly soluble salt.

The compounds can be formulated for parenteral administration byinjection, conveniently intravenous, intramuscular or subcutaneousinjection, for example by bolus injection or continuous intravenousinfusion. Formulations for injection can be presented in unit dosagefrom, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical compositions can take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and cancontain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the compounds may be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

The compounds can also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glyceride.

For intranasal administration, the compounds can be used, for example,as a liquid spray, as a powder or in the form of drops.

For administration by inhalation, the compounds can be convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbondioxide or other suitable gas. In the case of a pressurized aerosol thedosage unit can be determined by providing a valve to deliver a meteredamount. Capsules and cartridges of, e.g., gelatin for use in an inhaleror insulator can be formulated containing a powder mix of the retinoidcompound and a suitable powder base such as lactose or starch.

Aqueous suspensions can include pharmaceutically acceptable excipientssuch as suspending agents, e.g., sodium carboxymethyl cellulose,methylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents such as naturally occurring phosphatide, e.g., lecithin,or condensation products of an alkylene oxide with fatty acids, e.g.,polyoxyethylene stearate, or condensation products of ethylene oxidewith long chain aliphatic alcohols, e.g, heptadecaethylene-oxycetanol,or condensation products of ethylene oxide with partial esters derivedfrom fatty acids and a hexitol, e.g., polyoxyethylene sorbitol monoleateor condensation products of ethylene oxide with partial esters derivedfrom fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitanmonoleate. The aqueous suspensions can also contain one or morepreservatives, e.g., ethyl- or -n-propyl-p-hydroxy benzoate, one or morecoloring agents, one or more flavoring agents and one or more sweeteningagents, such as sucrose, saccharin or sodium or calcium cyclamate.

The compounds will be administered in an amount which is at a levelbelow the RAR activating threshold and at or above the RXR effectivedose in accordance with the invention. These amounts can be determinedby one skilled in the art.

The following are non-limiting embodiments of the invention:

EXAMPLE 1 Prophetic Example

While not intending to be bound by any particular theory, one aspect ofthe instant invention contemplates that TARGRETIN®, particularly at highdoses, activates RARs in addition to RXRs and this activation of RAR iswhy the non-responsive group (those with low triglyceride elevation) haddecreased survival in the pivotal TARGRETIN® clinical trials.

At a dose of 400 mg/m²/d, TARGRETIN® C_(max) values in the blood areestimated to be around 8,000 nM, at which concentration there will besignificant activation of RARs by TARGRETIN. Also, since the estimatedTARGRETIN® C_(max) values are around 2,000 nM at the lower dose (225mg/m²/d), some detrimental activation of RARs would occur even at thisdose.

Accordingly, it is envisioned that a patient could be dosed withTARGRETIN® to determine the RAR activating threshold and the RXReffective dose for the patient; administering to the patient the RXRagonist at a level below the RAR activating threshold and at or abovethe RXR effective dose.

EXAMPLE 2

3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrah-ydronaphth-7-yl]2(E),4(E)heptadienoic acid (VTP 194204) is a highly potent (EC₅₀=0.1-0.5 nM) andspecific RXR pan-agonist. VTP 194204 is believed to be readily used atpurely RXR-activating doses.

Pre-Clinical Pharmacology

VTP 194204 exhibits tumor growth inhibitory effects in cell linesderived from a variety of tumor types and in animal models of breast andlung cancer. Also in models of cancer-induced cachexia, VTP 194204maintained body weight, prevented loss of muscle and adipose tissue,improved food consumption, and prolonged survival. The anti-tumor andanti-cachectic properties of VTP 194204 are illustrated in FIG. 1.Preliminary studies indicate that the anti-cachectic properties of VTP194204 are independent of its anti-tumor effects.

Pre-Clinical Safety

IND-enabling safety evaluation and toxicokinetic studies have beencompleted. No genotoxicity was observed in a battery of tests (Ames,mouse lymphoma TK, and rat micronucleus assays). Repeated oral dosestudies for 4 weeks followed by recovery indicated the severe toxicdoses of VTP 194204 to be greater than 200 mg/m²/d and 60 mg/m²/d indogs and rats, respectively. These studies support a starting dose of 6mg/m²/d for the initial phase I-IIa dose escalation study.

Clinical Development Plan

The clinical plan will focus on achieving initial registration approvalfor treatment of NSCLC patients in a fourth-line setting. The initialPhase I-IIa study in NSCLC patients who have failed other therapies willbe a dose-escalation study to determine a pharmacologically effectivedose (full activation of RXRs as ascertained by pharmacodynamic markers)for VTP 194204. Preliminary survival data, in comparison to historicalcontrols, will be obtained from the study.

The Phase II/III registration study in fourth-line NSCLC patients(n=−160) will compare VTP 194204 versus best supportive care withcrossover upon disease progression. Approval will be based on a primaryendpoint of progression-free survival. Subsequent or parallel studieswill seek to expand clinical indications for VTP 194204 in NSCLC (e.g.,combination with platinum-based therapies or Tarceva®),cancer-associated cachexia and breast cancer.

EXAMPLE 3 Prophetic Example

A Phase 1-2a Study of the Safety, Pharmacokinetics and PharmacologicallyEffective Dose of Oral VTP 194204 in Patients with Advanced, MetastaticRefractory Non-Small Cell Lung Cancer (NSCLC)

Introduction

VTP 194204, a second-generation rexinoid, is a potent, specific fullagonist at all three (α, β and γ) retinoid X receptors (RXRs). VTP194204 exhibited tumor growth inhibitory effects in cell lines derivedfrom a variety of tumor types and in animal models of breast and lungcancer. Also in models of cancer-induced cachexia, VTP 194204 maintainedbody weight, prevented loss of muscle and adipose tissue, improved foodconsumption, and prolonged survival. This Phase I-IIa clinical trial isdesigned to determine the safety, pharmacokinetics, andpharmacologically effective dose of VTP 194204 for the treatment ofNSCLC patients through activation of RXRs.

Study Design

Study Endpoints

Primary:

To determine the safety of VTP 194204 administered orally on a dailyschedule.

To determine the pharmacologically effective dose (PED) of VTP 194204administered orally on a daily schedule.

To evaluate the pharmacokinetic profile of VTP 194204 in cancerpatients.

Secondary:

To determine the effects of VTP 194204 on survival of NSCLC patients.

To determine anti-tumor activity of VTP 194204 as manifested by standardresponse criteria, or by tumor markers.

Patient Selection:

Number of Patients: Patients will be entered into the study in cohortsof 1 to 3. The total number of patients entered will be determined bythe number of dose escalations

Condition/Disease:

Patients will be those with NSCLC refractory to standard therapies.

Inclusion Criteria:

Histologically confirmed NSCLC refractory to conventional therapy.

Male or female, 18 to 75 years of age, inclusive.

ECOG Performance Status 0-2.

Life expectancy >8 weeks.

Hematology: Hemoglobin ≧8.5 g/dl

Platelets ≧100,000 cells/mm³

Neutrophils ≧1500 cells/mm³

PT and PTT within normal limits, except for patients receiving COUMADIN®(warfarin sodium, Bristol Myers Squibb) for thromboembolic prophylaxisonly, in whom INR of less than 2 will be allowable.

Biochemistry: Total bilirubin 1.5×ULN

AST/ALT≦3.0×ULN

Serum creatinine ≦2.0 mg/dl

Serum calcium <11.5 mg/dl

Fasting serum triglycerides ≦2.5×ULN

Endocrine: Thyroid stimulating hormone (TSH) WNL (>0.5 mU/L and <5.5mU/L).

Negative urine pregnancy test for women of child-bearing potential atscreening and on Day 0, and agreement to use two reliable forms ofcontraception during therapy and for 1 month following discontinuationof therapy unless abstinence is the chosen birth control method.

Exclusion Criteria:

Major surgery within previous 4 weeks; large field radiation therapy(>25% of the patient's total marrow) or chemotherapy (includinginvestigational agents or participation in another clinical study)within previous 4 weeks; mitomycin C or nitrosoureas within 6 weeks.

Systemic retinoid therapy, or vitamin A at dosages >5,000 IU per day,during previous 4 weeks.

Patients with any prior or current history of thyroid disease, with anyhistory of pituitary disease, or with any history of prior or currenttreatment with thyroid replacement hormone.

Primary brain tumors, active brain metastasis including progression fromlast scan or evidence of cerebral edema, or clinical symptoms of brainmetastasis. Patients with prior history of brain metastasis must havebrain imaging (e.g., CT, MRI) performed.

Requirement for steroids or anticonvulsant medication. (Patients takingstable dosages of GnRH analogues or MEGACE® (megestrol acetate, BristolMyers Squibb) for at least the previous 3 months will be allowed intothe study).

Current enrollment in an investigational drug or device study orparticipation in such a study within 30 days of entry into this study.

Known HIV-positive patients.

Females who are pregnant, nursing, or planning a pregnancy.

History of gastrointestinal disorders (medical disorders or extensivesurgery) which may interfere with absorption of study medication.

Clinically significant abnormalities on screening ECG.

Treatment

Definitions

PED: defined as the dose at which 90% of all TSH measurements in allpatients in a 4-week cycle were 90% below the corresponding basal TSHvalues provided that at 50% of this dose at least 75% of all TSHmeasurements in all patients in a 4-week cycle were 80% below thecorresponding basal TSH values. It is expected that effective activationof RXRs will occur at a PED.

DLT: defined as one of the following toxicities (all toxicities gradedaccording to the NCI Common Toxicity Criteria, version 2.0 except theRAR biomarkers):

(1) More than 2-fold increase in levels of at least one RAR biomarker(e.g., CYP 26A, CD38).

(2) Any symptomatic Grade 2 toxicity that requires hold or reduction ofstudy drug administration.

(3) Any Grade 3 or higher symptomatic toxicity (excludingnausea/vomiting in the absence of optimal anti-emetics).

(4) Any Grade 3 asymptomatic biochemical (except SGOT (AST) or SGPT(ALT)) or hematologic toxicity persisting >7 days.

(5) SGOT (AST)/SGPT (ALT)>10×ULN (upper limit of normal range).

(6) Any Grade 4 biochemical or hematologic toxicity.

MTD: defined as the highest dose level at which less than 2 of a cohortof patients experience a dose-limiting toxicity (DLT) during a minimumperiod of 4 weeks. This means for a dose to meet the definition of MTD,the study drug will have been administered at that dose to a cohort ofat least three patients for at least 4 weeks and only one patient willhave experienced only one DLT during that time interval. This willgenerally be one dose level below that at which DLT occurs in 2patients. There is no specified minimum duration of study drug exposurerequired for consideration of a case of DLT for the determination of theMTD.

The derivation of a recommended dose for future studies will incorporatetolerability of the drug over 8 weeks in at least 3 patients. Thus, ifthe proposed recommended dose has fewer than 3 patients treated for atleast 8 weeks, additional patients will be enrolled at that dose level.

Duration:

A treatment cycle will be 4 weeks of daily oral study drugadministration (Cycle 1) in the absence of dose-limiting toxicity (DLT).After 4 weeks, patients may be allowed to continue on study in 4-weekincrements of daily oral study drug administration at the same doselevel (or reduced dose level) if further treatment is judged to be ofpossible clinical benefit (Cycles 2-12) to a maximum of 12 cycles.

Dosage/Dose Regimen:

Three patients will be accrued at each dose level. The initial dailydose of VTP 194204 will be approximately 0.2 mg/m²/day taken as asingle, oral dose. Doses will be escalated as described below. In theabsence of toxicity greater than Grade 2 on the NCI toxicity scale overa period of 4 weeks, the dose will be escalated by 100% for one to threepatients in each subsequent cohort. No intra-patient dose escalationwill be allowed from one cycle to the next. After a given cycle,patients may be allowed to continue on study in further increments offour weeks at the same dose as in the previous cycle, if theinvestigator determines it to be in the patient's interests to continuein the study. The initial dose and all subsequent dose escalations willbe to the nearest capsule size.

Thyroid hormone and thyroid stimulating hormone (TSH) levels, biomarkersof RXR activation, will be measured weekly in all patients duringCycle 1. In addition, levels of potential biomarkers for retinoic acidreceptor (RAR)-specific activity such as retinoic acid-induciblecytochrome P450 enzyme (CYP26A), cellular retinol binding protein-I(CRBPI), CD38, and RAR γ2 will be simultaneously monitored in bloodcells at the messenger RNA level by quantitative PCR assays. At a givendose level, if 75% or greater of all TSH measurements in all patients ina 4-week cycle are 80% below the corresponding basal TSH values and nopatient exhibits toxicity greater than Grade 2, then a further doseescalation of 100% will be made in a new cohort of 3 additionalpatients. If 90% of all TSH measurements in all patients in a 4-weekcycle at this new dose are 90% below the corresponding basal TSH values,then a pharmacologically effective dose (PED) will be deemed to havebeen reached. If not, further dose escalations of 100% (or of lesseramounts) will be made in new cohorts of 3 patients each until a PED asdefined above is reached unless a dose limiting toxicity (DLT) isreached earlier. The DLT is defined as equal or greater than 2-foldincrease in a RAR biomarker level and/or Grade 3 toxicity whichever isreached first. If a PED is reached prior to a DLT, 6 more patients willbe enrolled at the PED in order to further validate the PED.

If a patient develops a DLT, 3 additional patients will be enrolled atthat dose level. If none of the 3 additional patients develops a DLTover a period of 4 weeks, the dosage will continue to be escalated 100%for one to three patients in the subsequent cohorts. However, if 1, 2,or all 3 additional patients develop DLT, the dosage will be escalatedby 50% in a new cohort of 3 patients. Dose escalation will be carriedout until a dose equivalent to PED is reached, unless a dose limitingtoxicity (DLT) is reached earlier.

If one of the patients entered at a dose level experiences DLT, up to 3additional patients will be entered at that dose level. If none of the 3additional patients experiences a DLT, dose escalation will proceed witha dose increment of 33% in at least 3 patients per dose level. However,if a second patient in the cohort experiences DLT, then the maximumtolerated dose (MTD) will be deemed to be exceeded. Dose reduction dueto DLT or intolerability will be 50% unless a 50% dose reduction willresult in dosing at a previously investigated level, then a 33% dosereduction will be investigated.

Visit Schedule:

Patients will be seen for assessment every 7 days (+/−1 day) for 28days. Thus, there will be 6 scheduled visits (including screening visit)to the end of the first cycle. Those patients who continue on treatmentafter 28 days will be seen every 14 days (+/−2 days), or more frequentlyif clinically required.

Prophetic Results

The following are predicted, not actual, results:

PED is 1 mg/m²/d. The blood concentration of VTP 194204 at the PED is3±1 ng/mL. There was no discernible increase of levels of RAR biomarkersat any of the VTP 194204 dosages including the PED. Thus, dosages of VTP194204 of approximately 1 mg/m²/day are considered to be purelyRXR-activating dosages (i.e., no RAR activation). Such dosages areoptimal for treating NSCLC patients. The average median survival for theNSCLC patients in this study was 8.5 months compared to approximately 4months for historical, matched control patients.

EXAMPLE 4 Prophetic Example

A Randomized Phase III Trial Comparing VTP 194204/Carboplatin/Paclitaxelversus Carboplatin/Paclitaxel in Chemotherapy-Naive Patients withAdvanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

Introduction

VTP 194204, a second-generation rexinoid, is a potent, specific fullagonist at all three retinoid X receptors. VTP 194204 exhibited tumorgrowth inhibitory effects in cell lines derived from a variety of tumortypes and in animal models of breast and lung cancer. Also in models ofcancer-induced cachexia, VTP 194204 maintained body weight, preventedloss of muscle and adipose tissue, improved food consumption, andprolonged survival. A Phase III trial is designed to demonstrate thesurvival benefit of the addition of VTP 194204 to carboplatin/paclitaxelchemotherapy.

Study Design:

Patient Selection

Patients are selected to meet all following conditions

NSCLC at Stage IIIB with pleural effusion or Stage IV;

No prior chemotherapy;

ECOG=0, 1.

Treatment:

Patients stratified by disease stage and gender are randomized toreceive VTP 194204 once daily at a pure RXR-activating dose andcarboplatin AUC 6 and paclitaxel 200 mg/m², i.e., every 3 weeks orcarboplatin/paclitaxel alone. The pure RXR activation dose of VTP 194204is determined by monitoring induction of hypothyroidism (reduction inTSH levels), a pharmacological biomarker for RXR activation, in theabsence of induction of RAR biomarkers in blood.

Study Endpoints:

Primary endpoint: Overall survival

Secondary endpoint: Kaplan-Meier projected two-year survival rates.

Prophetic Results:

The predicted, not actual, clinical results are presented in TABLE 2:

TABLE 2 PROPHETIC, NOT ACTUAL, RESULTS Two-Year Median Survival SurvivalTreatment Group (Months) Rates (%) Carboplatin/Paclitaxel 9.2 16 VTP194204/Carboplatin/Paclitaxel 15 30

While the above description contains many specifics, these specificsshould not be construed as limitations of the invention, but merely asexemplifications of preferred embodiments thereof. Those skilled in theart will envision many other embodiments within the scope and spirit ofthe invention as defined by the claims appended hereto. Allpublications, patents and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication or patent application were specificallyand individually designated as having been incorporated by reference.

What is claimed is:
 1. A method of treating pancreatic cancer, themethod comprising administering to a patient in need of such treatment aretinoid X receptor (RXR) agonist at a dose which does not activateretinoic acid receptors (RAR) and wherein the dose of the RXR agonist isfrom about 1 to about 20 mg/m²/day, wherein the RXR agonist has achemical structure

or a pharmaceutically acceptable salt thereof.
 2. The method accordingto claim 1, wherein the dose is determined by dosing the patient withincreasing concentrations of a RXR agonist until an RXR effective doseis reached which does not activate RAR.
 3. The method according to claim2, wherein the RXR effective dose is determined by measuring reductionof a patient's TSH levels or at least one RAR biomarker expressed by thepatient.
 4. The method according to claim 3, wherein the RAR biomarkeris selected from the group consisting of CYP26 level, CRBPI level andcombinations thereof.
 5. The method according to claim 1, furthercomprising measuring the patient's C_(max) of the RXR agonist, andadjusting the dose to maintain the patient's C_(max) , at an optimallevel.
 6. The method according to claim 1, further comprising treatingthe patient with at least one other agent selected from the groupconsisting of anti-cancer agents, triglyceride lowering agents and TSHmodulating agents.
 7. The method according to claim 6, wherein theanti-cancer agent is selected from the group consisting of aplatinum-based compound, a cytotoxic drug, and mixtures thereof.
 8. Themethod according to claim 1, wherein the dose of the RXR agonist is fromabout 1 to about 10 mg/m²/day.
 9. The method according to claim 1,wherein the dose of the RXR agonist is from about 10 to about 20mg/m²/day.
 10. The method according to claim 1, wherein the RXR agonistis3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl](E),4(E) heptadienoic acid.